It has been recognized since the beginning of the AIDS epidemic that the brain may be an important reservoir for the human immunodeficiency virus (HIV). Drug development for treatment of HIV infection has progressed to the remarkable pace of two to three drugs being introduced in the clinic every year. However, we currently know very little about their ability to cross the blood brain and brain-cerebrospinal fluid barriers and almost nothing about their ability to enter susceptible cells in the brain, form active metabolites within these cells, or their ability to incorporate into HIV DNA and inhibit its replication. In this proposal we will examine each of six clinically used antiretroviral nucleoside analogs targeted against the reverse transcriptase enzyme and determine their ability to enter human glial cells, to form active metabolites, and to control HIV infection in these cells.